Evaluation of BCGΔBCG1419c::ESAT6-PE25SS in immunocompetent and immunocompromised mouse models of TB
Led by Dr Ana Maria Valencia Hernandez (James Cook University, Australia), with Dr Socorro Miranda-Hernandez (James Cook University, Australia), Dr Guangzu Zhao (James Cook University, Australia), Dr Andreas Kupz (James Cook University, Australia), and Dr Mario Flores-Valdez (CIATEJ, Mexico)
Project Aim
Tuberculosis (TB) is a major health concern that causes more than 1.5 million deaths each year. Vaccination is considered one of the most effecctive ways to eliminate TB. However, the only licensed TB vaccine, called BCG, provides limited protection against the disease in adults and can cause dangerous side effects in people with weaker immune systems. Therefore, there is an urgent need to develop a new vaccine that can overcome these problems. Recent animal studies published by others and us, have shown that modified versions of BCG can induce more protection against TB and less side effects in mice with weakened immune systems, than the original BCG vaccine. In a close collaboration between the research groups of Dr Mario Alberto Flores-Valdez at the CIATEJ, Mexico, and Dr Andreas Kupz at the AITHM, Australia, we have recently combined two of these modified BCG vaccines into one that is predicted to be an outstanding vaccine candidate. This project aims to investigate whether this new vaccine candidate can induce a stronger immune response and better protection against TB in mice with normal immune systems and is well-tolerated in mice with compromised immune systems, when compared with the original BCG vaccine. The results from this project will inform whether more comprehensive in vivo studies in other animal models of TB and future clinical trials are warranted.
Project Outcomes
Preliminary results from the immunogenicity studies revealed higher frequencies of effector memory cells (capable of killing infected cells) in spleens and lungs of mice vaccinated with the new vaccine strain BCGΔBCG1419c::ESAT6-PE25 (from now on named Delta19::PE25). Similar frequencies were found in mice vaccinated with parental strain BCGΔBCG1419c (from now on named Delta19). Mtb infections experiments in vaccinated mice suggest similar protection capacity by the different rBCG compared to conventional BCG. Mice vaccinated with the new strain Delta19::PE25 contained significantly fewer Mtb bacilli in lung and spleen compared to un-vaccinated mice. Similarly, analysis of damage lung area by histopathology showed that all BCG strains reduce inflammation to a similar level compared to un-vaccinated infected mice. Safety experiments in immunocompromised mice lacking B, T and NK cells revealed that the new vaccine strain Delta19::PE25 induces less weight loss compared to conventional BCG. Additionally, bacterial persistence after vaccination with rBCG strains in immunocompetent mice showed that the new vaccine strain Delta19::PE25 induced lower bacterial burden than mice receiving BCGΔBCG1419c::ESAT6-PE25 in spleen and lungs.
In vivo studies for the evaluation of the immunogenicity, efficacy and safety of the new vaccine candidate have been completed. However, further analysis into the immunogenicity parameters governing the immune responses in immunocompetent mice is still required. Despite no evidence suggesting that the new rBCG strain is more protective than conventional BCG against Mtb infection, studies in immunocompromised mice indicate this strain is safer than conventional BCG. These preliminary data warrants further comprehensive studies, including in models of reactivation of latent TB infection and comorbidity with type 2 diabetes.
